Key information
Research topics
Biochemistry & Proteomics Chemical Biology & High Throughput Synthetic Biology
A 2023 Crick PhD project with Charlie McTernan
Project background and description
We are a synthetic chemistry group working in supramolecular and biological chemistry, and nanotechnology. We work in the Francis Crick Institute in London, and at King's College London.
Our research looks at how we can apply Supramolecular Chemistry in Biological settings. Supramolecular Chemistry is the study of intermolecular, non-covalent interactions. These non-covalent interactions are critical to protein folding, DNA base pairing, and cellular signalling. Supramolecular Chemistry applies these same principles to create artificial systems capable of performing complex tasks. [1-3]
The McTernan Group aims to apply recent breakthroughs in artificial molecular machines and metal-organic capsules in biologically relevant settings. [4, 5] We work with rotaxanes, catenanes and capsules to synthesise functional architectures, creating de novo catalytic enzyme analogues, artificial cellular receptors, and generating targeted drug delivery vehicles.
The proposed project is at the nexus of several rapidly emerging areas of science: mechanically interlocked molecules, macrocyclic peptides, and supramolecular chemistry in biology. This project seeks to use cyclic peptides and depsipeptides as the macrocycles in rotaxanes (where a ring encircles a linear axle). This approach will have three key benefits over the current state-of-the-art, which uses simple macrocycles . Firstly, it will vastly increase the information density and complexity of the rotaxanes that we can form, thus enabling novel functions. Secondly, introducing mechanical bonds to cyclic peptide drug molecules will act as a new approach to solve current issues of stability, toxicity and bioavailability, by providing an orthogonally tunable handle. Thirdly, this programme will act as a first step to bridge the current divide between biological molecular machines (which evolved to function in aqueous environments) and artificial molecular machines (which function almost exclusively in organic solvents), by using intrinsically water-compatible components, constructing a new language for molecular machinery.
The current generation of interlocked molecules are almost exclusively formed from highly symmetric and simple macrocycles, such as crown ethers. [1] Whilst great progress has been made in biomedicine, technology, and molecular machinery by using information embedded in the axle, limited progress has been made with the other half of a rotaxane - the macrocyclic ring. The difficulty of selectively functionalising highly symmetric macrocycles, and often low yielding macrocyclisation reactions, have stymied progress in the area. Cyclic peptides provide a solution to both these difficulties - the synthesis of functional cyclic peptides is well established, amenable to solid-phase and high-throughput synthesis, and macrocyclisation is reliable and high yielding. As such, cyclic peptides provide an ideal platform to explore the transformative potential of highly functionalised and functional macrocycles in artificial molecular machines.
Candidate background
This project would suit candidates with a background in chemistry or biochemistry, and an interest in working at the interface between disciplines. An interest in organic synthesis would be an asset, as would a willingness to learn new techniques.
References
1. Erbas-Cakmak, S., Leigh, D.A., McTernan, C.T. and Nussbaumer, A.L. (2015)
Artificial Molecular Machines.
Chemical Reviews 115: 10081-10206. PubMed abstract
2. Erbas-Cakmak, S., Fielden, S.D.P., Karaca, U., Leigh, D.A., McTernan, C.T., Tetlow, D.J. and Wilson, M.R. (2017)
Rotary and linear molecular motors driven by pulses of a chemical fuel.
Science 358: 340-343. PubMed abstract
3. Fielden, S.D.P., Leigh, D.A., McTernan, C.T., Pérez-Saavedra, B. and Vitorica-Yrezabal, I.J. (2018)
Spontaneous assembly of rotaxanes from a primary amine, crown ether and electrophile.
Journal of the American Chemical Society 140: 6049-6052. PubMed abstract
4. McTernan, C.T., Ronson, T.K. and Nitschke, J.R. (2019)
Post-assembly modification of phosphine cages controls host-guest behavior.
Journal of the American Chemical Society 141: 6837-6842. PubMed abstract
5. McTernan, C.T., De Bo, G. and Leigh, D.A. (2020)
A track-based molecular synthesizer that builds a single-sequence oligomer through iterative carbon-carbon bond formation.
Chem 6: 2964-2973.
